Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper presents experimental investigations to evaluate fibrin seal for bleeding control under systemic heparinization as well as some of the benefits and limits of fibrin-presealing vascular prostheses. Local hemostasis using fibrin seal plus collagen fleece was achieved in 3 standardized sources of bleeding produced in mongrel dogs under full heparinization. Water porosity was measured in 3 standard prosthetic materials of different porosity. It could be shown that all graft types investigated were sufficiently sealed up to a pressure of 600 mmHg. The influence of fibrinolysis on the stability of the fibrin network in vascular grafts was tested by in vitro experiments using urokinase incubation. While water permeability increased in fibrin-sealed fabric without aprotinin added, no fibrinolysis-induced leakage was observed in those exposed to aprotinin. Surface thrombogenicity of the fibrin-sealed grafts was higher than in blood-preclotted prostheses, if not rinsed with isotonic saline. After rinsing, thrombogenicity decreased below values obtained in grafts preclotted conventionally. Survival studies in animals show no difference between blood-preclotted and fibrin-presealed prostheses both 3 and 7 days after implantation.
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PMID:Evaluation of fibrin seal in animal experiments. 618 30

Plasminogen is present in the cornea andcan be activated to plasmin by plasminogen activator. Plasmin is able, in turn, to activate latent collagenase. This system could initiate and perpetuate the collagen degradation of corneal ulceration. This report details evidence for such a system in the cornea. Plasmin has been found to activate latent collagenase from organ cultures of ulcerating rabbit corneas and from fibroblast cultures derived from such corneas. As in the case of activation by trypsin, activation by plasmin results in the conversion of the 40,000 MW latent form to an active species of 23,000 MW. Explants of normal or alkali-burned, ulcerating corneas demonstrated plasminogen-dependent lysis of fibrin clots; frozen sections of such corneas demonstrated that lysis begins in the superficial stroma near the periphery of the cornea. Multiply freeze-thawed ulcerating corneas, but not normal corneas, showed initial lysis, not peripherally but at the ulcer region containing polymorphonuclear leukocytes. The fact that the peripheral lytic pattern existed in corneas that were obtained from eyes prefrozen in liquid nitrogen before excision of the corneas would suggest that plasminogen activator is normally contained in cells in vivo and is not made only in response to tissue injury. There was no correlation between the location of blood vessels or the presence of the corneal endothelium and the plasminogen-dependent lysis. Plasminogen activator from the ulcerating cornea and from fibroblasts was characterized by sodium dodecyl sulfate--gel electrophoresis of its cleavage products of plasminogen. The activator cleaves plasminogen into heavy- and light-chain fragments similar to those produced from plasminogen by urokinase. Plasminogen activator activity was quantitated by a new assay that restricts diffusion of the enzyme to one dimension into a narrow bore tube. The addition of plasminogen daily to cultures of ulcerating corneas resulted in earlier rises of plasminogen activator, collagenase, and collagen degradation fragments in the culture media. Although total plasminogen activator levels were not increased by the addition of plasminogen to culture, levels of both collagenase and solubilized collagen were approximately doubled. It is concluded that the plasminogen activator--plasmin system might play an important role in the destruction of stromal matrix in corneal ulceration.
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PMID:Evidence for a role of the plasminogen activator--plasmin system in corneal ulceration. 625 12

Tumor cells traverse basement membranes (BM) during the stages of the metastatic process. Penetration of the BM may involve proteolysis by enzymes directly or indirectly associated with tumor cells. This study evaluated the role of the serine proteases urokinase (plasminogen activator), plasmin, and another regulatory protease, alpha-thrombin, in the degradation of the BM. Homogeneously pure enzyme preparations were incubated with isolated components of BM and with whole human amnion BM. The BM components consisted of acid-extracted type IV collagen, pepsin fragments of collagen type IV, laminin, and fibronectin. Collagen type V (alpha A alpha B) associated with the peri-BM zone was also studied. The purity of the enzymes was verified by gel electrophoresis and inhibitor studies. Digestion of the BM components was performed at 25 degrees using matched activity for the different enzymes. Urokinase failed to significantly degrade fibronectin or any of the other BM components. Under the same 25 degrees (native) conditions, plasmin and thrombin cleaved fibronectin and laminin into multiple specific fragments but did not produce a major cleavage of acid-extracted type IV collagen, pepsinized type IV collagen, or alpha A alpha B (type V) collagade fibronectin or any of the other BM components. Under the same 25 degrees (native) conditions, plasmin and thrombin cleaved fibronectin and laminin into multiple specific fragments but did not produce a major cleavage of acid-extracted type IV collagen, pepsinized type IV collagen, or alpha A alpha B (type V) collagade fibronectin or any of the other BM components. Under the same 25 degrees (native) conditions, plasmin and thrombin cleaved fibronectin and laminin into multiple specific fragments but did not produce a major cleavage of acid-extracted type IV collagen, pepsinized type IV collagen, or alpha A alpha B (type V) collagen. alpha-Thrombn selectively degraded only the m.w. 400,000 chain of laminin, whereas plasmin degraded both the laminin chains. Digestion of laminin by the serine proteases was time and concentration dependent, as verified by a new degradation assay using [14C]laminin. A variety of normal and neoplastic cells were tested for the presence of laminin-degrading proteases. macrophages, polymorphonuclear leukocytes, and metastatic tumor cells contained a significant laminin-degarding activity. The activity was enhanced by the addition of plasminogen. Type V collagen was cleaved by thrombin and plasmin at 35 degrees but not at temperatures below 33 degrees. Following treatment of whole-amnion BM with any of these enzymes, electron microscopy demonstrated preservation of the lamina densa. Immunohistology studies indicated that laminin, but not type IV collagen, was removed from the whole BM by plasmin treatment. The results suggest that these BM components are poor substrates for plasminogen activators and that plasmin alone is not sufficient to completely degrade the whole BM...
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PMID:Effect of plasminogen activator (urokinase), plasmin, and thrombin on glycoprotein and collagenous components of basement membrane. 645 54

With a view to developing biomaterials for semipermanent substitution, we have studied a composite material constituted with collagen and a synthetic polymer which possesses high tissue compatibility. This collagen-synthetic polymer composite was applied as a support for immobilization of enzymes for the purpose of providing a material surface with biological function. The enzymes, urokinase and trypsin, were successfully bound to the collagen membrane layer which had been activated by acyl azide formation of its carboxyl groups. The enzyme-bearing composite material showed excellent catalytic activity toward a protein substrate as well as a low-molecular-weight synthetic substrate. The immobilized urokinase was characterized enzymatically and compared with native urokinase. The apparent affinity of immobilized urokinase for the substrate was slightly decreased, but its intrinsic kinetic properties were not significantly affected. No decrease in its esterase activity was observed both on repeated use and on long-term storage, and its fibrinolytic activity was stable on heat or disinfection treatment. When this urokinase-bearing composite material was applied into rabbit blood vessels, its in vivo fibrinolytic activity was maintained. Thus, enzyme-collagen-synthetic polymer composites may find wide application for biomaterials and artificial organs as functional biomaterials.
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PMID:The in vitro and in vivo behavior of urokinase immobilized onto collagen-synthetic polymer composite material. 702 80

The aim of the present study was to determine whether angiogenic cytokines, which induce neovascularization in the blood vascular system, might also be operative in the lymphatic system. In an assay of spontaneous in vitro angiogenesis, endothelial cells isolated from bovine lymphatic vessels retained their histotypic morphogenetic properties by forming capillary-like tubes. In a second assay, in which endothelial cells could be induced to invade a three-dimensional collagen gel within which they formed tube-like structures, lymphatic endothelial cells responded to basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in a manner similar to what has previously been observed with endothelial cells derived from the blood vascular system. Finally, since angiogenesis is believed to require extracellular proteolytic activity, we investigated the effects of bFGF and VEGF on lymphatic endothelial cell proteolytic properties by focussing on the plasminogen activator (PA) system. bFGF and VEGF increased urokinase, urokinase receptor, and tissue-type PA expression. This was accompanied by an increase in PA inhibitor-1, which is thought to play an important permissive role in angiogenesis by protecting the extracellular matrix against excessive proteolytic degradation. Taken together, these results demonstrate that with respect to in vitro morphogenetic and proteolytic properties, lymphatic endothelial cells respond to the previously described angiogenic factors, bFGF and VEGF, in a manner very similar to what has been described for endothelial cells derived from the blood vascular system.
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PMID:In vitro angiogenic and proteolytic properties of bovine lymphatic endothelial cells. 750 53

Epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha) stimulated cell migration, chemotaxis, and the expression of tissue-type plasminogen activator (t-PA) in human omental microvascular endothelial (HOME) cells. Hepatocyte growth factor (HGF) stimulated cell proliferation, but had a negligible stimulatory effect on cell migration, the expression of t-PA and tube-like formation into collagen gel in HOME cells. Basic fibroblast growth factor stimulated cell proliferation, cell migration, tubulogenesis and the expression of urokinase-type plasminogen activator (u-PA) in bovine aortic endothelial (BAE) cells. HOME and BAE cells had both high- and low-affinity receptors for HGF. In BAE cells, u-PA activity and tube-like structures in collagen gel were induced in the presence of HGF alone. In contrast, in HOME cells, t-PA activity and tube-like structures were induced in the presence of TGF-alpha alone, but not in the presence of HGF alone. However, we observed a marked induction of tube formation by HOME cells when both t-PA and HGF were added simultaneously. In the model system for tumor angiogenesis, when HOME cells were co-cultured with a renal cancer cell line, KPK13, tube-like structures were induced in the presence of HGF:KPK13 cells expressed large amounts of t-PA mRNA. Our present study suggested that HGF in concert with active t-PA could be angiogenic in HOME cells.
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PMID:Cooperative roles of hepatocyte growth factor and plasminogen activator in tubular morphogenesis by human microvascular endothelial cells. 750 7

Pulmonary fibrosis was induced in male Sprague-Dawley rats by intratracheal instillation of bleomycin. By 30 d post-bleomycin, the lungs exhibited elevated interstitial collagen levels. Thirty d after exposure to bleomycin, animals were further treated by intratracheal administration of phosphate-buffered saline (PBS) or 12,500 units of recombinant human urokinase (rh-UK). Three days later, the animals were sacrificed and the lungs fixed, sectioned, and assessed for fibrosis. The presence of interstitial collagen was quantitated using a BioQuant Image Analysis System (R and M Biometrics, Inc., Nashville, TN). Urokinase treatment of animals with established pulmonary fibrosis induced by exposure to 0.5 units of bleomycin was found to diminish the collagen content of lungs to near control levels by 3 d post-UK treatment. By 36 d post-UK treatment (66 d post-bleomycin), values for interstitial collagen were again partially elevated, indicating that UK treatment interfered with established fibrosis but did not stop the bleomycin-mediated process. However, the extent of fibrosis was less than that observed in lungs from non-UK treated animals 66 d post-bleomycin. UK treatment initiated 63 d post-bleomycin exposure again revealed a decline in the extent of fibrosis, but the values did not return to baseline levels. A repeat of the short-term experiment with a higher dose of bleomycin (0.85 units) again revealed that UK treatment was effective in diminishing the extent of fibrosis from 22% to 12% collagen. These results indicate that exogenous UK may be an effective therapeutic modality in the treatment of pulmonary fibrosis induced by some stimuli or developing in association with diseases such as scleroderma.
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PMID:Partial reversal of established bleomycin-induced pulmonary fibrosis by rh-urokinase in a rat model. 751 75

Induction of differentiation of F9 teratocarcinoma stem cells by retinoic acid and cAMP has been shown to involve the activation of the transcription factor AP-1 (a heterodimer of the proto-oncogene products c-Fos and c-Jun); moreover, stable expression of either Fos or Jun drives F9 cells into differentiation. Phorbol ester tumor promoters and short-wave-length ultraviolet (uv) irradiation are efficient inducers of AP-1 activity in various differentiated cells, but it has been shown that phorbol esters do not induce AP-1 activity in undifferentiated F9 cells. We examine here whether uv irradiation induces AP-1 activity in these cells and drives F9 cells into differentiation. We show that uv induces, in contrast to phorbol esters, the formation of active AP-1 by activating transcription from the c-jun gene. Ultraviolet-induced AP-1 drives transcription from AP-1-dependent promoters coding for differentiation-associated proteins (such as urokinase and keratin 18). However, in uv-treated cells, these genes are activated earlier and to a greater extent than in cells treated with retinoic acid and cAMP. More importantly, uv, in contrast to retinoic acid and cAMP, does not induce the accumulation of collagen alpha 1 (IV) and laminin B1 RNA. Our data suggest that the c-jun gene in F9 cells is accessible to immediate activation, but that uv-induced AP-1 activation does not suffice to induce the full program of F9 cell differentiation.
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PMID:Ultraviolet irradiation, although it activates the transcription factor AP-1 in F9 teratocarcinoma stem cells, does not induce the full complement of differentiation-associated genes. 752 41

Angiogenin is a potent angiogenic molecule in the chick chorioallantoic membrane assay and rabbit corneal assay. However, no angiogenic activity has been reported in in vitro system. In this study, we isolated and purified angiogenin from bovine milk, and the biological effect of the bovine angiogenin on bovine endothelial cells was examined in in vitro angiogenesis models. Bovine angiogenin significantly stimulated both cell migration and formation of tube-like structures in the collagen gel by bovine aortic endothelial cells. Angiogenin at 10-100 ng/ml stimulated about 2-fold higher the tube formation when basic fibroblast growth factor (bFGF) at 10 ng/ml stimulated about 3-fold over the control. Tubular morphogenesis stimulated by bFGF or angiogenin was almost completely blocked in the presence of aprotinin, an inhibitor of serine proteases. Angiogenin up-regulated both mRNA level and activity of urokinase type plasminogen activator, a key mediator of angiogenesis. Moreover, both bFGF and bovine angiogenin induced a marked increase of c-fos mRNA level at 30 min after stimulation. These novel effects of bovine angiogenin are to be discussed in relation to its structure specificity.
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PMID:Modulation by bovine angiogenin of tubular morphogenesis and expression of plasminogen activator in bovine endothelial cells. 754 Aug 39

Dissemination of tumor cells includes several steps, such as: (a) detachment of tumor cells from the primary tumor, (b) traversement of the basement membrane, and (c) migration into the extracellular matrix. In these processes, at least two important categories of proteins are involved: proteases and adhesion molecules. In this contribution we describe the expression and function of components of the plasminogen activator (PA) system (proteases) and of integrins (cell-matrix adhesion molecules) in a panel of four human melanoma cell lines with different invasive and metastatic capacity. Regarding the components of the PA system, we found differences in expression of urokinase-type PA (uPA) and type 1 and 2 PA inhibitors (PAI-1 and -2) between metastasizing and nonmetastasizing cell lines. Both components were exclusively expressed in the highly invasive and metastatic cell lines. Interestingly, studies on the expression of PA components in fresh human melanocytic lesions, showed expression of these components exclusively in advanced primary melanomas and melanoma metastases. Regarding integrin expression we found elevated levels of VLA-2 and VLA-6 in the highly invasive and metastatic cell lines compared with normal cultured melanocytes and nonmetastatic melanoma cell lines. In addition, increased adhesion of the highly metastatic cell lines to laminin (LM) and collagen (COLL) was observed. Furthermore, reduced adhesion of normal melanocytes and nonmetastatic melanoma cells to LM and CO was mainly due to the fact that the integrins involved in adhesion to these matrix components were present in an inactive state. Finally, differences were observed in expression of integrins involved in adhesion to fibronectin.
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PMID:Properties of metastasizing and nonmetastasizing human melanoma cells. 759 84


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